Intrinsic and environmental influences on thymocyte migration signatures

细胞迁移对包括细胞和组织发育在内的许多生物过程都很重要。迁移细胞的行为有令人难以置信的多样性：一些细胞迁移得很慢，另一些细胞迁移得很快，一些细胞沿着相当笔直的路径移动到特定的目的地，而另一些细胞则曲折地迁移，没有明显的方向性，一些细胞单独迁移，而另一些细胞则是集体迁移。为什么某些迁移模式与特定的细胞类型相关联，以及哪些因素影响这些迁移特征，对于许多细胞子集没有很好的描述。作为一个解决这些生物学问题的模型，我们研究了一种称为T细胞的免疫细胞亚型在胸腺中发育时的迁移模式。播种胸腺的祖细胞通过一系列特征良好的发育中间体，胸腺细胞(未成熟T细胞)在发育的每个阶段都显示出不同的迁移特征。特别是在一个发育转变过程中，胸腺细胞从缓慢、曲折的细胞转变为以更快的直线移动的细胞，其速度增加了一倍以上，成为体内最快的细胞之一。这些发育阶段发生在胸腺的不同位置，但影响它们迁移特征的因素没有得到很好的描述。我们使用一种独特的器官培养系统和先进的显微镜技术来可视化发育中的T细胞在完整胸腺组织中的动态迁移，以确定影响迁移模式的因素，并确定调节这些迁移如何影响T细胞的发育。此外，基于细胞在完整组织中的迁移特征，我们应用图像分析和机器学习方法来识别异质群体中的细胞亚群。最终，这些研究将有助于我们理解细胞迁移是如何为发育中的T细胞、其他免疫细胞和其他细胞的正常发育和功能而优化的。此外，在这项研究计划的背景下，几名本科生和研究生将接受跨学科培训，使用最先进的技术，这些技术将使他们具备在加拿大新兴的免疫学和生物光子学领域出类拔萃所需的技能。

Cell migration is important for a number of biological processes including cell and tissue development. The behavior of migrating cells is incredibly diverse: some cells migrate slowly and others fast, some cells travel along a fairly straight path to a specific destination while others migrate tortuously with no obvious directionality, and some migrate individually whereas others move as a group. Why certain migration patterns are associated with particular cell types and what factors influence these migration signatures is not well described for many cell subsets. As a model to address these biological questions, we study the migration patterns of a subtype of immune cells called T cells as they develop in the thymus. The progenitor cells that seed the thymus transit through a series of well-characterized developmental intermediates, and thymocytes (immature T cells) at each stage of development display distinct migration signatures. During one developmental transition in particular, thymocytes more than double their speed transitioning from slow, meandering cells into cells that move with increased straightness and become among the fastest cells in the body. These developmental stages occur in distinct locations in the thymus, but the factors that influence their migratory signatures are not well described. We use a unique organ culture system and advanced microscopy techniques to visualize the dynamic migration of developing T cells in intact thymus tissue in order to identify the factors that influence migration patterns and determine how modulating these movements influence T cell development. In addition, we apply image analyses and machine learning approaches to identify cell subsets within a heterogeneous population based on their migration signature in intact tissue. Ultimately, these studies will contribute to our understanding of how cell migration is optimized for proper development and function of developing T cells, other immune cells, and beyond. Further, in the context of this research program several undergraduate and graduate students will receive interdisciplinary training using state-of-the-art technologies that will equip them with the skills they need to excel in the burgeoning fields of immunology and biophotonics in Canada.